Acetaminophen causes fulminant hepatic necrosis in man and animal models via a chemically reactive metabolite formed in the liver by a minor cytochrome P-450 dependent pathway of metabolism. Major metabolic pathways in vivo lead to nontoxic metabolites (the 4-0-glucuronide and -sulfate). Recent studies have developed an isolated hamster hepatocyte system which has been crucial in development of the principle that inhibition of, or deficiency in, activity of the competing nontoxic pathways of acetaminophen metabolism is a prime determinant of the susceptibility of hamsters to the drugs hepatotoxicity. It is proposed to use the hamster animal model and the isolated hepatocyte system to examine further the kinetic and pharmacokinetic relationships between acetaminophen metabolism and formation of its toxic reactive metabolite as a basis for 1) other possible drug-acetaminophen interactions which may enhance acetaminophen hepatotoxicity, 2) the development of more specific experimental tools to be used to manipulate drug metabolism in animals in order to develop animal models for other drug-induced hepatotoxicity, 3) the examination of the mechanisms of action of current therapy for acetaminophen overdosage, and 4) several aspects of structure/toxicity relationships for acetaminophen analogues. Other studies will consider the applicability of the above principle as a determinant of susceptibility to acetaminophen-hepatotoxicity in man, and the factors in the animal model which determine the glutathione protective capacity of the liver. Finally, an animal model for oxyphenisatin-induced liver necrosis, developed using the above principle will be used to determine the mechanism underlying oxyphenisatin hepatotoxicity.